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Selected Publication:
Borowski, P; Deinert, J; Schalinski, S; Bretner, M; Ginalski, K; Kulikowski, T; Shugar, D.
Halogenated benzimidazoles and benzotriazoles as inhibitors of the NTPase/helicase activities of hepatitis C and related viruses.
Eur J Biochem. 2003; 270(8):1645-53
Doi: 10.1046/j.1432-1033.2003.03540.x
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- Co-authors Med Uni Graz
- Heinze Sarah
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- Abstract:
- A search has been initiated for lead inhibitors of the nonstructural protein 3 (NS3)-associated NTPase/helicase activities of hepatitis C virus, the related West Nile virus, Japanese encephalitis virus and the human mitochondrial Suv3 enzyme. Random screening of a broad range of unrelated low-molecular mass compounds, employing both RNA and DNA substrates, revealed that 4,5,6,7-tetrabromobenzotriazole (TBBT) hitherto known as a potent highly selective inhibitor of protein kinase 2, is a good inhibitor of the helicase, but not NTPase, activity of hepatitis C virus NTPase/helicase. The IC50 is approximately 20 micro m with a DNA substrate, but only 60 micro m with an RNA substrate. Several related analogues of TBBT were enzyme- and/or substrate-specific inhibitors. For example, 5,6-dichloro-1-(beta-d-ribofuranosyl)benzotriazole (DRBT) was a good, and selective, inhibitor of the West Nile virus enzyme with an RNA substrate (IC50 approximately 0.3 micro m), but much weaker with a DNA substrate (IC50 approximately 3 micro m). Preincubation of the enzymes, but not substrates, with DRBT enhanced inhibitory potency, e.g. the IC50 vs the hepatitis C virus helicase activity was reduced from 1.5 to 0.1 micro m. No effect of preincubation was noted with TBBT, suggesting a different mode of interaction with the enzyme. The tetrachloro congener of TBBT, 4,5,6,7,-tetrachlorobenzotriazole (TCBT; a much weaker inhibitor of casein kinase 2) is also a much weaker inhibitor than TBBT of all four helicases. Kinetic studies, supplemented by comparison of ATP-binding sites, indicated that, unlike the case with casein kinase 2, the mode of action of the inhibitors vs the helicases is not by interaction with the catalytic ATP-binding site, but rather by occupation of an allosteric nucleoside/nucleotide binding site. The halogeno benzimidazoles and benzotriazoles included in this study are excellent lead compounds for the development of more potent inhibitors of hepatitis C virus and other viral NTPase/helicases.
- Find related publications in this database (using NLM MeSH Indexing)
- Acid Anhydride Hydrolases - antagonists & inhibitors
- Adenosine Triphosphatases - antagonists & inhibitors, chemistry
- Antiviral Agents - pharmacology
- Benzimidazoles - pharmacology
- Binding Sites - administration & dosage
- DNA Helicases - antagonists & inhibitors
- Hepacivirus - drug effects, enzymology
- Kinetics - administration & dosage
- Models, Molecular - administration & dosage
- Nucleoside-Triphosphatase - administration & dosage
- Protein Conformation - administration & dosage
- Substrate Specificity - administration & dosage
- Triazoles - pharmacology
- Viral Nonstructural Proteins - antagonists & inhibitors, chemistry
- Find related publications in this database (Keywords)
- NTPase/helicases
- hepatitis C and related viruses
- inhibitors
- halogenated benzimidazoles/benzotriazoles